The airway epithelium expresses a considerable H+ conductance localized in the apical membrane where it contributes to acid release into the airway surface liquid. In April 2006 a H+ channel gene (HVCN1) was identified. Our preliminary data suggest that HVCN1 is the H+ channel found in the airways. This application explores the contribution of HVCN1 to the airway H+ conductance and its physiological function. Both our preliminary data and the described function of the H+ channel in phagocytes suggest that the H+ channel in the airways supports the NADPH oxidase DUOX1, and is thus part of airway defenses. Our general hypothesis is that HVCN1 codes for the airway epithelial H+ channel and HVCN1 supports the NADPH oxidase DUOX1. Our specific aims are to 1) molecularly identify, express, and functionally characterize the HVCN1 H+ channel of the human airway epithelium, and 2) determine the role of the HVCN1 H+ channel in DUOX1 function. These aims test a model in which HVCN1 is necessary for the DUOX1-based airway defenses. The proposed studies will be done by a combination of molecular biology approaches, cell culture techniques, and electrophysiological and fluorescence microscopy methods. This study will result in information about the identity of the airway H+ channel, its function, and its proposed role in airway defense. The results of this study will have public health relevance because ineffective bacterial defenses are commonly found in airway diseases. PUBLIC HEALTH RELEVANCE. The innate defenses of the airways are crucial to prevent infection of the lungs with airborne pathogens, which is an important area of public health. This project will investigate a novel mechanism of airway defenses focused on the function of the proton channel of the airways, which may in the long-term lead to therapeutic applications in inflammatory airway diseases, such as cystic fibrosis or asthma.